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Research & Scholarship

Current Research and Scholarly Interests

In the United States, cancer continues to be the leading cause of death in patients between 25 and 64 years of age, and the second leading cause of death in patients both above 65 years and between 1 and 14 years. Since prognosis and survival of patients with cancer highly depend on the tumor stage at the time of diagnosis, early cancer detection shows great promise in prolonging survival and improving quality of life in cancer patients. Therefore, novel imaging strategies are highly desirable that allow detection of cancer at early, still curable stages. Furthermore, with the advent of novel therapeutic options for cancer patients there is an increasing demand for non-invasive imaging biomarkers to identify those patients early on that benefit most from a given treatment or to terminate or modify treatment for those patients not responding to a certain treatment.In my laboratory we focus on the development and clinical translation of novel molecular and functional imaging biomarkers with special focus on imaging abdominal and pelvic cancer including pancreatic, liver, renal, ovarian, and prostate cancer. We further advance clinically available radiological imaging modalities such as ultrasound, magnetic resonance imaging (MRI), and positron emission tomography (PET) as promising imaging tools for early detection and treatment monitoring of abdominal and pelvic cancer. Our mission is to integrate novel molecular and functional imaging strategies into clinical protocols for improved patient care in the near future.

Clinical Trials

B-mode Ultrasound Imaging in Detecting Early Liver CancerRecruiting

This pilot trial studies how well B-mode ultrasound imaging works in detecting liver cancer
that is early in its growth and may not have spread to other parts of the body. Diagnostic
procedures, such as B-mode ultrasound imaging, may help find and diagnose liver cancer and
find out how far the disease has spread.

This clinical trial studies ultrasound elastography in diagnosing patients with kidney or
liver solid focal lesions. New diagnostic procedures, such as ultrasound elastography, may
be a less invasive way to check for kidney or liver solid focal lesions.

Perfusion CT as a Predictor of Treatment Response in Patients With Hepatic MalignanciesNot Recruiting

A research study of liver perfusion (how blood flows to the liver over time). We hope to
learn whether perfusion characteristics of liver masses may be predictive of response to
treatment and whether liver perfusion characteristics can be used to follow response to
treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Elizabeth Chitouras, 650-498-0623.

Patients are invited to participate in a research study of liver perfusion (how blood flows
to the liver over time). Researchers hope to learn whether perfusion characteristics of
liver metastases may be predictive of response to treatment and whether liver perfusion
characteristics can be used to follow response to treatment. Patients were selected as a
possible participant in this study because they are identified as having liver metastases

Perfusion CT as a Predictor of Treatment Response in Patients With Rectal CancerNot Recruiting

A research study of rectal cancer perfusion (how blood flows to the rectum over time). We
hope to learn whether perfusion characteristics of rectal masses may be predictive of
response to treatment and whether rectal perfusion characteristics can be used to follow
response to treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Laura Gable, 650-736-0798.

The purpose of this study is to demonstrate the Sensitivity and Specificity of
SonoVue®-enhanced ultrasound is superior to that of unenhanced ultrasound for the
characterization of benign versus malignant FLLs using final diagnosis based on histology or
combined imaging (CE-CT and/or CE MRI)/clinical data as truth standard.

Stanford is currently not accepting patients for this trial.For more information, please contact Lindee Burton, (650) 725 - 4712.

Primary Objective:
The primary objectives of this prospective pilot study is to:
1. determine the feasibility and reproducibility of 3D contrast enhanced ultrasound
imaging in liver cancer patients undergoing Stereotactic Ablative Radiotherapy and
2. evaluate whether there are treatment induced early changes in imaging metrics derived
from 3D contrast enhanced ultrasound. This study will provide valuable insight as to
the potential of baseline and/or early post-treatment 3D ultrasound perfusion
characteristics (measurements of blood-flow) of primary and metastatic liver tumors to
predict tumor response to Stereotactic Ablative Radiotherapy. The investigators'
underlying goal is to assess whether early perfusion changes at 1-7 days after SABR
initiation can be used as a non-invasive early biomarker for treatment response
assessment.
Secondary Objectives:
Evaluate the feasibility of contrast-enhanced ultrasound-to-CT fusion by assisting
three-dimensional (3D) perfusion ultrasound (US) imaging with optical and electromagnetic
tracking of the ultrasound probe on patients with liver cancer that will undergo CT for
treatment planning and/or response evaluation.

Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool
for cancer detection and monitoring response to therapy. Sodium Fluorine-18 (F-18) was used
in the 1970s for bone scanning and can be used as a skeletal tracer in current PET/CT
scanners. The combined administration of F-18 and F-18 FDG in a single PET/CT scan for
cancer detection was not attempted to date. We hope to learn what is the best approach for
detection of cancer and thus to improve cancer treatment.

Abstract

Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non-coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound-guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P<0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA-loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5-9 fold (P<0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti-apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC.

Abstract

Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

Abstract

Ultrasound and combined optical and ultrasonic (photoacoustic) molecular imaging have shown great promise in the visualization and monitoring of cancer through imaging of vascular and extravascular molecular targets. Contrast-enhanced ultrasound with molecularly targeted microbubbles can detect early-stage cancer through the visualization of targets expressed on the angiogenic vasculature of tumors. Ultrasonic molecular imaging can be extended to the imaging of extravascular targets through use of nanoscale, phase-change droplets and photoacoustic imaging, which provides further molecular information on cancer given by the chemical composition of tissues and by targeted nanoparticles that can interact with extravascular tissues at the receptor level. A new generation of targeted contrast agents goes beyond merely increasing imaging signal at the site of target expression but shows activatable and differential contrast depending on their interactions with the tumor microenvironment. These innovations may further improve our ability to detect and characterize tumors. In this review, recent developments in acoustic and photoacoustic molecular imaging of cancer are discussed.

Abstract

Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P

Abstract

Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies.

Abstract

To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD).All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor ? antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence.Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (? = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (? = 0.69; P = .04). Colonic wall thickness (P ? .06), bowel wall perfusion (P ? .85), and clinical disease activity scoring (P ? .06) were not significantly different between treated and nontreated mice at any time.Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.

Abstract

Critically ill patients are commonly imaged for liver dysfunction. An often fatal condition, secondary sclerosing cholangitis, is an important and likely under-recognized hepatic condition in these patients. In presenting this case report, we hope to raise awareness of this condition amongst radiologists as well as other physicians caring for the critically ill.

Abstract

Therapeutic efficacy of both traditional chemotherapy and gene therapy in cancer is highly dependent on the ability to deliver drugs across natural barriers, such as the vessel wall or tumor cell membranes. In this regard, sonoporation induced by ultrasound-guided microbubble (USMB) destruction has been widely investigated in the enhancement of therapeutic drug delivery given it can help overcome these natural barriers, thereby increasing drug delivery into cancer. In this chapter we discuss challenges in current cancer therapy and how some of these challenges could be overcome using USMB-mediated drug delivery. We particularly focus on recent advances in delivery approaches that have been developed to further improve therapeutic efficiency and specificity of various cancer treatments. An example of clinical translation of USMB-mediated drug delivery is also shown.

Abstract

Molecularly-targeted microbubbles (MBs) are increasingly being recognized as promising contrast agents for oncological molecular imaging with ultrasound. With the detection and validation of new molecular imaging targets, novel binding ligands are needed that bind to molecular imaging targets with high affinity and specificity. In this study we assessed a novel class of potentially clinically translatable MBs using an engineered 10(th) type III domain of human-fibronectin (MB-FN3VEGFR2) scaffold-ligand to image VEGFR2 on the neovasculature of cancer. The in vitro binding of MB-FN3VEGFR2 to a soluble VEGFR2 was assessed by flow-cytometry (FACS) and binding to VEGFR2-expressing cells was assessed by flow-chamber cell attachment studies under flow shear stress conditions. In vivo binding of MB-FN3VEGFR2 was tested in a transgenic mouse model (FVB/N Tg(MMTV/PyMT634Mul) of breast cancer and control litter mates with normal mammary glands. In vitro FACS and flow-chamber cell attachment studies showed significantly (P<0.01) higher binding to VEGFR2 using MB-FN3VEGFR2 than control agents. In vivo ultrasound molecular imaging (USMI) studies using MB-FN3VEGFR2 demonstrated specific binding to VEGFR2 and was significantly higher (P<0.01) in breast cancer compared to normal breast tissue. Ex vivo immunofluorescence-analysis showed significantly (P<0.01) increased VEGFR2-expression in breast cancer compared to normal mammary tissue. Our results suggest that MBs coupled to FN3-scaffolds can be designed and used for USMI of breast cancer neoangiogenesis. Due to their small size, stability, solubility, the lack of glycosylation and disulfide bonds, FN3-scaffolds can be recombinantly produced with the advantage of generating small, high affinity ligands in a cost efficient way for USMI.

Abstract

To identify and evaluate sonographic features suggestive of extracapsular extension in papillary thyroid cancer.Three board-certified radiologists blinded to the final pathologic tumor stage reviewed sonograms of pathologically proven cases of papillary thyroid cancer for the presence of extracapsular extension. The radiologists evaluated the following features: capsular abutment, bulging of the normal thyroid contour, loss of the echogenic capsule, and vascularity extending beyond the capsule.A total of 129 cases of pathologically proven thyroid cancer were identified. Of these, 51 were excluded because of lack of preoperative sonography, and 16 were excluded because of pathologic findings showing anaplastic carcinoma, follicular carcinoma, or microcarcinoma (<10 mm). The final analysis group consisted of 62 patients with papillary thyroid carcinoma, 16 of whom had pathologically proven extracapsular extension. The presence of capsular abutment had 100% sensitivity for detection of extracapsular extension. Conversely, lack of capsular abutment had a 100% negative predictive value (NPV) for excluding extracapsular extension. Contour bulging had 88% sensitivity for detection of extracapsular extension and when absent had an 87% NPV. Loss of the echogenic capsule was the best predictor of the presence of extracapsular extension, with an odds ratio of 10.23 (P= .034). This sonographic finding had 75% sensitivity, 65% specificity, and an 88% NPV. Vascularity beyond the capsule had 89% specificity but sensitivity of only 25%.Sonographic features of capsular abutment, contour bulging, and loss of the echogenic thyroid capsule have excellent predictive value for excluding or detecting extracapsular extension and may help in biopsy selection, surgical planning, and treatment of patients with papillary thyroid cancer.

Abstract

The purpose of this study was to test the hypothesis that soft-tissue infiltration along the celiac plexus and delayed enhancement exceeding two-thirds of the tumor area on preoperative MDCT correlate with histologic evidence of perineural invasion in resected intrahepatic cholangiocarcinomas.Two experienced abdominal radiologists retrospectively reviewed preoperative multiphasic MDCT scans of 20 patients who underwent resection of intrahepatic cholangiocarcinoma, identifying soft-tissue infiltration along the celiac plexus, delayed enhancement exceeding two-thirds of the tumor area, and maximum tumor diameter. Consensus findings were compared with intratumoral perineural invasion in resected intrahepatic cholangiocarcinomas using the Fisher exact test.Six patients had histologic intratumoral perineural invasion, five of whom had soft-tissue infiltration along the celiac plexus on preoperative MDCT, with corresponding 83.3% sensitivity and 92.9% specificity for perineural invasion and significant association between these MDCT and histologic findings (p = 0.002). No patients with histologic perineural invasion had enhancement exceeding two-thirds of the tumor area on MDCT; sensitivity was 0.0% for this finding. Tumor diameter on MDCT was not significantly associated with perineural invasion at histopathology (p = 0.530).Soft-tissue infiltration along the celiac plexus on MDCT is an indicator of perineural invasion in patients with intrahepatic cholangiocarcinoma. The data did not confirm an association between delayed enhancement exceeding two-thirds of the tumor area and perineural invasion. Because perineural invasion from intrahepatic cholangiocarcinoma is associated with a very poor prognosis and is generally a contraindication to surgery, the MDCT diagnosis of celiac plexus perineural invasion in patients with intrahepatic cholangiocarcinoma may have important implications for prognosis and treatment planning.

Abstract

Ultrasound is a widely available, cost-effective, real-time, non-invasive and safe imaging modality widely used in the clinic for anatomical and functional imaging. With the introduction of novel molecularly-targeted ultrasound contrast agents, another dimension of ultrasound has become a reality: diagnosing and monitoring pathological processes at the molecular level. Most commonly used ultrasound molecular imaging contrast agents are micron sized, gas-containing microbubbles functionalized to recognize and attach to molecules expressed on inflamed or angiogenic vascular endothelial cells. There are several potential clinical applications currently being explored including earlier detection, molecular profiling, and monitoring of cancer, as well as visualization of ischemic memory in transient myocardial ischemia, monitoring of disease activity in inflammatory bowel disease, and assessment of arteriosclerosis. Recently, a first clinical grade ultrasound contrast agent (BR55), targeted at a molecule expressed in neoangiogenesis (vascular endothelial growth factor receptor type 2; VEGFR2) has been introduced and safety and feasibility of VEGFR2-targeted ultrasound imaging is being explored in first inhuman clinical trials in various cancer types. This review describes the design of ultrasound molecular imaging contrast agents, imaging techniques, and potential future clinical applications of ultrasound molecular imaging.

Abstract

We have developed a novel orthotopic rat hepatocellular (HCC) model and have assessed the ability to use bioluminescence imaging (BLI), positron emission tomography (PET), and ultrasound for early tumor detection and monitoring of disease progression. Briefly, rat HCC cells were stably transfected with click beetle red as a reporter gene for BLI. Tumor cells were injected under direct visualization into the left or middle lobe of the liver in 37 rats. In six animals, serial PET, BLI, and ultrasound imaging were performed at 10-time points in 28 days. The remainder of the animals underwent PET imaging at 14 days. Tumor implantation was successful in 34 of 37 animals (91.9%). In the six animals that underwent serial imaging, tumor formation was first detected with BLI on Day 4 with continued increase through Day 21, and hypermetabolic activity on PET was first noted on Days 14-15 with continued increase through Day 28. PET activity was seen on Day 14 in the 28 other animals that demonstrated tumor development. Anatomic tumor formation was detected with ultrasound at Days 10-12 with continued growth through Day 28. The first metastases were detected by PET after Day 24. We have successfully developed and validated a novel orthotopic HCC small animal model that permits longitudinal assessment of change in tumor size using molecular imaging techniques. BLI is the most sensitive imaging method for detection of early tumor formation and growth. This model permits high-throughput in vivo evaluation of image-guided therapies.

Abstract

Sodium fluoride PET (F-NaF) has recently reemerged as a valuable method for detection of osseous metastasis, with recent work highlighting the potential of coadministered F-NaF and F-FDG PET/CT in a single combined imaging examination. We further examined the potential of such combined examinations by comparing dual tracer F-NaF/F-FDG PET/CT with CT alone for detection of osseous metastasis.Seventy-five participants with biopsy-proven malignancy were consecutively enrolled from a single center and underwent combined F-NaF/F-FDG PET/CT and diagnostic CT scans. PET/CT as well as CT only images were reviewed in blinded fashion and compared with the results of clinical, imaging, or histological follow-up as a truth standard.Sensitivity of the combined F-NaF/F-FDG PET/CT was higher than that of CT alone (97.4% vs 66.7%). CT and F-NaF/F-FDG PET/CT were concordant in 73% of studies. Of 20 discordant cases, F-NaF/F-FDG PET/CT was correct in 19 (95%). Three cases were interpreted concordantly but incorrectly, and all 3 were false positives. A single case of osseous metastasis was detected by CT alone, but not by F-NaF/F-FDG PET/CT.Combined F-NaF/F-FDG PET/CT outperforms CT alone and is highly sensitive and specific for detection of osseous metastases. The concordantly interpreted false-positive cases demonstrate the difficulty of distinguishing degenerative from malignant disease, whereas the single case of metastasis seen on CT but not PET highlights the need for careful review of CT images in multimodality studies.

Abstract

Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background.Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology.Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%).Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.

Abstract

Ultrasound mediated drug delivery using microbubbles is a safe and noninvasive approach for spatially localized drug administration. This approach can create temporary and reversible openings on cellular membranes and vessel walls (a process called "sonoporation"), allowing for enhanced transport of therapeutic agents across these natural barriers. It is generally believed that the sonoporation process is highly associated with the energetic cavitation activities (volumetric expansion, contraction, fragmentation, and collapse) of the microbubble. However, a thorough understanding of the process was unavailable until recently. Important progress on the mechanistic understanding of sonoporation and the corresponding physiological responses in vitro and in vivo has been made. Specifically, recent research shed light on the cavitation process of microbubbles and fluid motion during insonation of ultrasound, on the spatio-temporal interactions between microbubbles and cells or vessel walls, as well as on the temporal course of the subsequent biological effects. These findings have significant clinical implications on the development of optimal treatment strategies for effective drug delivery. In this article, current progress in the mechanistic understanding of ultrasound and microbubble mediated drug delivery and its implications for clinical translation is discussed.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

Abstract

Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.

Abstract

Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.

Abstract

Abstract Hypoxia-inducible factor-1 alpha (HIF-1α) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1α expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1α-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1α gene (HIF-1α-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1α-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1α-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1α-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1α-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1α-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1α therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1α-VP2 therapy in preclinical models of myocardial ischemia.

Abstract

Two of the successful gene-directed enzyme prodrug therapies include herpes simplex virus-thymidine kinase (HSV1-TK) enzyme-ganciclovir prodrug and the Escherichia coli nitroreductase (NTR) enzyme-CB1954 prodrug strategies; these enzyme-prodrug combinations produce activated cytotoxic metabolites of the prodrugs capable of tumor cell death by inhibiting DNA synthesis and killing quiescent cells, respectively. Both these strategies also affect significant bystander cell killing of neighboring tumor cells that do not express these enzymes. We have developed a dual-combination gene strategy, where we identified HSV1-TK and NTR fused in a particular orientation can effectively kill tumor cells when the tumor cells are treated with a fusion HSV1-TK-NTR gene- along with a prodrug combination of GCV and CB1954. In order to determine whether the dual-system demonstrate superior therapeutic efficacy than either HSV1-TK or NTR systems alone, we conducted both in vitro and in vivo tumor xenograft studies using triple negative SUM159 breast cancer cells, by evaluating the efficacy of cell death by apoptosis and necrosis upon treatment with the dual HSV1-TK genes-GCV-CB1954 prodrugs system, and compared the efficiency to HSV1-TK-GCV and NTR-CB1954. Our cell-based studies, tumor regression studies in xenograft mice, histological analyses of treated tumors and bystander studies indicate that the dual HSV1-TK-NTR-prodrug system is two times more efficient even with half the doses of both prodrugs than the respective single gene-prodrug system, as evidenced by enhanced apoptosis and necrosis of tumor cells in vitro in culture and xenograft of tumor tissues in animals.

Abstract

Extrapancreatic perineural spread in pancreatic adenocarcinoma contributes to poor outcomes, as it is known to be a major contributor to positive surgical margins and disease recurrence. However, current staging classifications have not yet taken extrapancreatic perineural spread into account. Four pathways of extrapancreatic perineural spread have been described that conveniently follow small defined arterial pathways. Small field of view three-dimensional (3D) volume-rendered multidetector computed tomography (MDCT) images allow visualization of small peripancreatic vessels and thus perineural invasion that may be associated with them. One such vessel, the posterior inferior pancreaticoduodenal artery (PIPDA), serves as a surrogate for extrapancreatic perineural spread by pancreatic adenocarcinoma arising in the uncinate process. This pictorial review presents the normal and variant anatomy of the PIPDA with 3D volume-rendered MDCT imaging, and emphasizes its role as a vascular landmark for the diagnosis of extrapancreatic perineural invasion from uncinate adenocarcinomas. Familiarity with the anatomy of PIPDA will allow accurate detection of extrapancreatic perineural spread by pancreatic adenocarcinoma involving the uncinate process, and may potentially have important staging implications as neoadjuvant therapy improves.

Abstract

To evaluate the feasibility of 3D perfusion CT for predicting early treatment response in patients with liver metastasis from colorectal cancer.Seventeen patients with colon cancer and liver metastasis were prospectively enroled to undergo perfusion CT and 18F-FDG-PET/CT before and after one-cycle of chemotherapy. Two radiologists and three nuclear medicine physicians measured various perfusion CT and PET/CT parameters, respectively from the largest hepatic metastasis. Baseline values and reduction rates of the parameters were compared between responders and nonresponders. Spearman correlation test was used to correlate perfusion CT and PET/CT parameters, using RECIST criteria as reference standard.Nine patients responded to treatment, eight patients were nonresponders. Baseline SUVmean30 on PET/CT, reduction rates of 30% metabolic volume and 30% lesion glycolysis (LG30) on PET/CT and blood flow (BF) and flow extraction product (FEP) on perfusion CT after chemotherapy were significantly different between responders and nonresponders (P=0.008-0.046). Reduction rates of BF (correlation coefficient=0.630) and FEP (correlation coefficient=0.578) significantly correlated with that of LG30 on PET/CT (P<0.05).CT perfusion parameters including BF and FEP may be used as early predictors of tumor response in patients with liver metastasis from colorectal cancer.

Abstract

Ultrasound molecular imaging is increasingly used in preclinical studies to measure the expression of vascular markers during inflammation process. In this context, a new ultrasound contrast agent functionalized with a recombinant P-selectin glycoprotein ligand-1 analogue (rPSGL-Ig) was developed (MBrPSGL-Ig). This agent was assayed in vitro and in vivo to evaluate its binding performance and potential to image expression of inflammatory markers E- and P-selectin. Performance of this newly developed agent was compared with that of antibody (MBAb) or sialyl Lewis X (MBsLe) containing microbubbles and with control microbubbles (MBC).The targeted ultrasound contrast agents were prepared by coupling biotin-conjugated ligands onto streptavidin-functionalized microbubbles. First, in vitro experiments were performed to measure the adhesion efficiency of these microbubble constructs under static or flow conditions (114 sec), on cell monolayer (human umbilical vein endothelial cells and bEnd.5), or coatings of E- or P-selectin of various animal species, respectively. Second, molecular imaging studies were performed in a rat inflammatory model 24 hours after intramuscular injection of lipopolysaccharide in the hind limb. Finally, immunohistochemistry staining of rat inflamed muscle tissue was performed to assess expression of E- and P-selectin.Microbubbles functionalized with rPSGL-Ig (MBrPSGL-Ig) displayed firm in vitro binding on the coating of both recombinant E- or P-selectin, with an efficiency similar to microbubbles comprising antibody specific for E-selectin (MBE) or P-selectin (MBP). In contrast, lower binding capacity was measured with MBsLe. At the surface of inflamed endothelial cells, MBrPSGL-Ig were able to interact specifically with E- and P-selectin. Binding specificity was demonstrated by performing blocking experiments with target-specific antibodies, resulting in an 80% to 95% decrease in binding. Ten minutes after microbubble injection, echo signal measured with MBrPSGL-Ig in the inflamed muscles was 20-fold higher compared with MBC. Moreover, the in vivo adhesion of MBrPSGL-Ig was 2- and 7-fold higher compared with P-selectin or E-selectin-specific microbubbles, respectively. Immunohistochemistry revealed a temporal coexpression of E- and P-selectin in the vascular bed of inflamed rat muscle 24 hours after lipopolysaccharide injection.The molecular imaging study demonstrates that MBrPSGL-Ig provide imaging signal higher than those measured with antibody or sialyl Lewis X containing microbubbles. These results suggest that MBrPSGL-Ig is a powerful agent to image the expression of both E- and P-selectin in the context of an inflammatory process.

Abstract

Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of ?-catenin in cellular respiration or mitochondria of hepatocytes.We investigated ?-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of ?-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication).Under homeostatic conditions, ?-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with ?-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. ?-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-? signaling.?-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; ?-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-?-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.

Abstract

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ? 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.

Adenocarcinoma of the uncinate process of the pancreas: MDCT patterns of local invasion and clinical features at presentationEUROPEAN RADIOLOGYPadilla-Thornton, A. E., Willmann, J. K., Jeffrey, R. B.2012; 22 (5): 1067-1074

Abstract

To compare the multidetector CT (MDCT) patterns of local invasion and clinical findings at presentation in patients with adenocarcinoma of the uncinate process of the pancreas to patients with adenocarcinomas in the non-uncinate head of the pancreas.We evaluated the two cohorts for common duct and pancreatic duct dilatation, mesenteric vascular encasement, root of mesentery invasion, perineural invasion and duodenal invasion. In addition, we compared the clinical findings at presentation in both groups.Common duct (P?0.001) and pancreatic duct dilatation (P?=?0.001) were significantly less common in uncinate process adenocarcinomas than in the non-uncinate head of the pancreas. Clinical findings of jaundice (P?=?0.01) and pruritis (P?=?0.004) were significantly more common in patients with lesions in the non-uncinate head of the pancreas. Superior mesenteric artery encasement (P?=?0.02) and perineural invasion (P?=?0.001) were significantly more common with uncinate process adenocarcinomas.Owing to its unique anatomic location, adenocarcinomas within the uncinate process of the pancreas have significantly different patterns of both local invasion and clinical presentation compared to patients with carcinomas in the non-uncinate head of the pancreas. Key Points • SMA encasement and perineural invasion were more common with uncinate process adenocarcinomas. • Common bile duct and pancreatic duct dilatation were less common in uncinate process adenocarcinomas • Jaundice and pruritis were more common with lesions elsewhere in the pancreatic head.

Abstract

The purpose of this study was to review the CT findings and clinical outcome in patients with incidentally discovered solid pancreatic masses.Over an 8-year period, from 2001 to 2009, we identified 24 patients with solid pancreatic masses incidentally detected by CT. There were 13 females and 11 males, with a mean age of 67 years. We determined the indication for initial CT, analyzed the CT features, and ascertained the clinical follow-up in all the patients.All of the solid masses were malignant. There were 14 adenocarcinomas and 10 neuroendocrine tumors. The most common indications for the initial CT were surveillance of an extrapancreatic malignancy (n = 10) and evaluation for hematuria (n = 6). On the initial CT, 16 of the patients (67%) had a clearly visible pancreatic mass. In eight patients isoattenuating masses were identified, only recognized by subtle signs including unexplained dilatation of the pancreatic duct (n = 5) or minimal contour deformity or density of the pancreas (n = 3). The mean survival time for the patients with adenocarcinoma was 21.6 months, and 42 months for the patients with neuroendocrine tumors.Although uncommon, incidentally discovered solid pancreatic masses are malignant neoplasms, either ductal adenocarcinomas or neuroendocrine tumors. Unlike incidentally discovered small cystic lesions, solid pancreatic lesions are often biologically aggressive.

Abstract

Over the past decade, molecularly-targeted contrast enhanced ultrasound (ultrasound molecular imaging) has attracted significant attention in preclinical research of cancer diagnostic and therapy. Potential applications for ultrasound molecular imaging run the gamut from early detection and characterization of malignancies to monitoring treatment responses and guiding therapies. There may also be a role for ultrasound contrast agents for improved delivery of chemotherapeutic drugs and gene therapies across biological barriers. Currently, a first Phase 0 clinical trial in patients with prostate cancer assesses toxicity and feasibility of ultrasound molecular imaging using contrast agents targeted at the angiogenic marker vascular endothelial growth factor receptor type 2 (VEGFR2). This mini-review highlights recent advances and potential applications of ultrasound molecular imaging and ultrasound-guided therapy in cancer.

Abstract

PURPOSE: To develop and test a fast ultrasonic molecular imaging technique for quantification and monitoring of angiogenesis in cancer. MATERIALS AND METHODS: A new software algorithm measuring the dwell time of contrast microbubbles in near real-time (henceforth, fast method) was developed and integrated in a clinical ultrasound system. In vivo quantification and monitoring of tumor angiogenesis during anti-VEGF antibody therapy was performed in human colon cancer xenografts in mice (n=20) using the new fast method following administration of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast microbubbles. Imaging results were compared with a traditional destruction/replenishment approach (henceforth, traditional method) in an intra-animal comparison. RESULTS: There was excellent correlation (R(2)=0.93; P<0.001) between the fast method and the traditional method in terms of VEGFR2-targeted in vivo ultrasonic molecular imaging with significantly higher (P=0.002) imaging signal in colon cancer xenografts using VEGFR2-targeted compared to control non-targeted contrast microbubbles. The new fast method was highly reproducible (ICC=0.87). Following anti-angiogenic therapy, ultrasonic molecular imaging signal decreased by an average of 41±10%, whereas imaging signal increased by an average of 54±8% in non-treated tumors over a 72-hour period. Decreased VEGFR2 expression levels following anti-VEGF therapy were confirmed on ex vivo immunofluorescent staining. CONCLUSIONS: Fast ultrasonic molecular imaging based on dwell time microbubble signal measurements correlates well with the traditional measurement method, and allows reliable in vivo monitoring of anti-angiogenic therapy in human colon cancer xenografts. The improved work-flow afforded by the new quantification approach may facilitate clinical translation of ultrasonic molecular imaging.

Abstract

To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia.Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 ?L iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n=32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n=32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n=32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol.The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ? 0.006) and remained significantly decreased until day 7 (P ? 0.008); tumor volume increased significantly only on day 7 (P=0.04). After radiation treatment, all 3 perfusion parameters decreased significantly on day 1 (P < 0.001); BF and flow extraction product increased again on day 3 and 5, although without reaching statistically significant difference; and tumor volumes did not change significantly at all time points (P ? 0.3). In the control group, all 3 perfusion parameters did not change significantly, whereas tumor volume increased significantly at all the time points, compared with baseline (P ? 0.04). Ex vivo immunofluorescent staining showed good correlation between all 3 perfusion parameters and microvessel density (?=0.71, 0.66, and 0.69 for BF, BV, and flow extraction product, respectively; P < 0.001). There was a trend toward negative correlation between extent of hypoxia and all 3 perfusion parameters (?=-0.53, -0.47, and -0.40 for BF, BV, and flow extraction product, respectively; P ? 0.05).CT perfusion allows a reproducible, noninvasive assessment of tumor vascularity in human colon cancer xenografts in mice. After antiangiogenic and radiation therapy, BF, BV, and flow extraction product significantly decrease and change faster than the tumor volume.

Abstract

To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs.Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x10(8) MBs and by changing MB dose (1x10(7), 5x10(7), 1x10(8), or 5x10(8) MBs) while keeping a constant DNA dose of 50 µg.Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (? = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x10(8) MBs with no further significant increase with 5x10(8) MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x10(7) MBs (P = 0.02) to a factor of 1.4 for 1x10(8) MBs (P < 0.01) and no significant difference for 5x10(8) MBs.Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.

Abstract

We tested a novel imaging strategy, in which both the survival of transplanted myoblasts and their therapeutic transgene expression, a recombinant hypoxia-inducible factor-1? (HIF-1?-VP2), can be monitored using firefly luciferase (fluc) and Renilla luciferase (hrl) bioluminescence reporter genes, respectively.The plasmid pUbi-hrl-pUbi-HIF-1?-VP2, which expresses both hrl and HIF-1?-VP2 using two ubiquitin promoters, was characterized in vitro. C2c12 myoblasts stably expressing fluc and transiently transfected with pUbi-hrl-pUbi-HIF-1?-VP2 were injected into the mouse hindlimb. Both hrl and fluc expression were monitored using bioluminescence imaging (BLI).Strong correlations existed between the expression of hRL and each of HIF-1?-VP2, VEGF, and PlGF (r(2) > 0.83, r(2) > 0.82, and r(2) > 0.97, respectively). In vivo, both transplanted cells and HIF-1?-VP2 transgene expression were successfully imaged using BLI.An objective evaluation of myoblast-mediated gene transfer in living mice can be performed by monitoring both the survival and the transgene expression of transplanted myoblasts using the techniques developed herein.

Abstract

Ovarian cancer is the most lethal of the gynecologic malignancies. Because ovarian cancer symptoms are subtle and nonspecific, the diagnosis is often delayed until the disease is well advanced. Overall 5-year survival is a rather dismal 50% but can be improved to greater than 90% if the disease is confined to the ovary at the time of diagnosis (generally in fewer than 25% of patients). Effective screening tools are currently not available. Owing to the rather low incidence of the disease in the general population, potential screening tests must provide very high specificity to avoid unnecessary interventions in false-positive cases. This article reviews currently available serum biomarkers and imaging tests for the early detection of ovarian cancer and provides an outlook on the potential improvements in these noninvasive diagnostic tools that may lead to successful implementation in a screening program. Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11090563/-/DC1.

Abstract

Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01±0.61 versus 4.36±0.68; P<0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer.

Abstract

Transcriptional targeting for cardiac gene therapy is limited by the relatively weak activity of most cardiac-specific promoters. We have developed a bidirectional plasmid vector, which uses a two-step transcriptional amplification (TSTA) strategy to enhance the expression of two optical reporter genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery of an hrluc-enhanced variant of the vector, long-term fluc expression was observed in the heart, but not in the liver. In both the cardiac cell line and the myocardium, fluc expression correlated well with hrluc expression. These results show the vector's ability to effectively amplify and couple transgene expression in a cardiac-specific manner. Further replacement of either reporter gene with a therapeutic gene should allow non-invasive imaging of targeted gene therapy in living subjects.

Abstract

In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use positron-emission tomography (PET) or single photon-emission computed tomography (SPECT)-based techniques. In ongoing preclinical research, novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multi-modality molecular imaging. Contrast-enhanced molecular ultrasound (US) with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and US imaging with molecularly-targeted microbubbles are attractive strategies as they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and US techniques involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with US. Current preclinical findings and advances in instrumentation, such as endoscopes and microcatheters, suggest that these molecular imaging methods have numerous potential clinical applications and will be translated into clinical use in the near future.

Abstract

Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications.

Abstract

We tested the hypothesis that modulation of the microenvironment (using antioxidants) will increase stem cell survival in hypoxia and after transplantation to the myocardium.Rat cardiomyoblasts were stably transfected with a reporter gene (firefly luciferase) for bioluminescence imaging (BLI). First, we examined the role of oxidative stress in cells under hypoxic conditions. Subsequently, stem cells were transplanted to the myocardium of rats using high-resolution ultrasound, and their survival was monitored daily using BLI.Under hypoxia, oxidative stress was increased together with decreased cell survival compared to control cells, both of which were preserved by antioxidants. In living subjects, oxidative stress blockade increased early cell survival after transplantation to the myocardium, compared to untreated cells/animals.Modulation of the local microenvironment (with antioxidants) improves stem cell survival. Increased understanding of the interaction between stem cells and their microenvironment will be critical to advance the field of regenerative medicine.

Abstract

Targeted contrast-enhanced ultrasound imaging is increasingly being recognized as a powerful imaging tool for the detection and quantification of tumor angiogenesis at the molecular level. The purpose of this study was to develop and test a new class of targeting ligands for targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with small, conformationally constrained peptides that can be coupled to the surface of ultrasound contrast agents.Directed evolution was used to engineer a small, disulfide-constrained cystine knot (knottin) peptide that bound to alpha(v)beta(3) integrins with a low nanomolar affinity (Knottin(Integrin)). A targeted contrast-enhanced ultrasound imaging contrast agent was created by attaching Knottin(Integrin) to the shell of perfluorocarbon-filled microbubbles (MB-Knottin(Integrin)). A knottin peptide with a scrambled sequence was used to create control microbubbles (MB-Knottin(Scrambled)). The binding of MB-Knottin(Integrin) and MB-Knottin(Scrambled) to alpha(v)beta(3) integrin-positive cells and control cells was assessed in cell culture binding experiments and compared with that of microbubbles coupled to an anti-alpha(v)beta(3) integrin monoclonal antibody (MB(alphavbeta3)) and microbubbles coupled to the peptidomimetic agent c(RGDfK) (MB(cRGD)). The in vivo imaging signals of contrast-enhanced ultrasound with the different types of microbubbles were quantified in 42 mice bearing human ovarian adenocarcinoma xenograft tumors by use of a high-resolution 40-MHz ultrasound system.MB-Knottin(Integrin) attached significantly more to alpha(v)beta(3) integrin-positive cells (1.76 +/- 0.49 [mean +/- SD] microbubbles per cell) than to control cells (0.07 +/- 0.006). Control MB-Knottin(Scrambled) adhered less to alpha(v)beta(3) integrin-positive cells (0.15 +/- 0.12) than MB-Knottin(Integrin). After blocking of integrins, the attachment of MB-Knottin(Integrin) to alpha(v)beta(3) integrin-positive cells decreased significantly. The in vivo ultrasound imaging signal was significantly higher after the administration of MB-Knottin(Integrin) than after the administration of MB(alphavbeta3) or control MB-Knottin(Scrambled). After in vivo blocking of integrin receptors, the imaging signal after the administration of MB-Knottin(Integrin) decreased significantly (by 64%). The imaging signals after the administration of MB-Knottin(Integrin) were not significantly different in the groups of tumor-bearing mice imaged with MB-Knottin(Integrin) and with MB(cRGD). Ex vivo immunofluorescence confirmed integrin expression on endothelial cells of human ovarian adenocarcinoma xenograft tumors.Integrin-binding knottin peptides can be conjugated to the surface of microbubbles and used for in vivo targeted contrast-enhanced ultrasound imaging of tumor angiogenesis. Our results demonstrate that microbubbles conjugated to small peptide-targeting ligands provide imaging signals higher than those provided by a large antibody molecule.

Abstract

The purpose of this article is to familiarize radiologists with the common pathways of extrapancreatic perineural invasion of pancreatic adenocarcinoma and to highlight the potential value of 3D volume-rendered MDCT in its diagnosis.The perineural plexuses closely follow peripancreatic vessels, which are well depicted by contrast-enhanced 3D volume-rendered imaging, thus facilitating the diagnosis of extrapancreatic perineural invasion of pancreatic adenocarcinoma.

Abstract

To retrospectively compare, in a multiobserver study, double-contrast-material (sequential administration of ferucarbotran and gadobutrol) magnetic resonance (MR) imaging with single-contrast-material ferucarbotran-enhanced and dynamic postferucarbotran gadobutrol-enhanced MR imaging for the detection and characterization of benign and malignant focal liver lesions.This study was institutional review board approved, and the requirement for informed patient consent was waived. Eighty-nine patients with a total of 128 focal liver lesions underwent double-contrast liver MR imaging (nonenhanced, ferucarbotran-enhanced, and dynamic postferucarbotran gadobutrol-enhanced MR imaging performed during one session). Four readers independently reviewed the data sets during three reading sessions focused on focal liver lesion detection and characterization: In session 1, the nonenhanced and dynamic postferucarbotran gadobutrol-enhanced images obtained at double-contrast MR imaging were analyzed. In session 2, the nonenhanced and ferucarbotran-enhanced images were analyzed. In session 3, all MR images were analyzed together. The diagnostic performance of each MR technique and each reader was evaluated by using receiver operating characteristic (ROC) analysis; differences between postferucarbotran gadobutrol-enhanced, ferucarbotran-enhanced, and double-contrast MR imaging were assessed at Wilcoxon signed rank testing; and interreader agreement was assessed at Cohen kappa analysis. Histopathologic confirmation or an unchanged clinical course or MR finding was the reference standard.The four readers' detection of the benign and malignant lesions was not significantly different (P > or = .11) between the three MR techniques. The benign and malignant focal liver lesions were differentiated with significantly higher confidence (P < or = .01) on the double-contrast (area under ROC curve [A(z)] = 0.988) and ferucarbotran-enhanced (A(z) = 0.985) MR images than on the dynamic gadobutrol-enhanced images (A(z) = 0.963). Accuracy in the diagnosis of hepatocellular carcinoma (HCC) was highest (P = .02) and confidence in the final diagnosis of HCC (P = .001) or metastasis (P = .049) was significantly higher with double-contrast imaging.In select cases, double-contrast MR imaging can improve diagnostic accuracy and increase confidence in characterizing focal liver lesions as HCC or metastasis.

Abstract

The purpose of the study was to retrospectively compare three-dimensional gadolinium-enhanced magnetic resonance angiography (conventional MRA) with MRA accelerated by a parallel acquisition technique (fast MRA) for the assessment of visceral arteries, using 64-detector-row computed tomography angiography (MDCTA) as the reference standard. Eighteen patients underwent fast MRA (imaging time 17 s), conventional MRA (29 s) and MDCTA of the abdomen and pelvis. Two independent readers assessed subjective image quality and the presence of arterial stenosis. Data were analysed on per-patient and per-segment bases. Fast MRA yielded better subjective image quality in all segments compared with conventional MRA (P = 0.012 for reader 1, P = 0.055 for reader 2) because of fewer motion-induced artefacts. Sensitivity and specificity of fast MRA for the detection of arterial stenosis were 100% for both readers. Sensitivity of conventional MRA was 89% for both readers, and specificity was 100% (reader 1) and 99% (reader 2). Differences in sensitivity between the two types of MRA were not significant for either reader. Interobserver agreement for the detection of arterial stenosis was excellent for fast (kappa = 1.00) and good for conventional MRA (kappa = 0.76). Thus, subjective image quality of visceral arteries remains good on fast MRA compared with conventional MRA, and the two techniques do not differ substantially in the grading of arterial stenosis, despite the markedly reduced acquisition time of fast MRA.

Abstract

The use of regulated gene expression systems is important for successful gene therapy applications. In this study, ligand-induced structural change in the estrogen receptor (ER) was used to develop a novel ER intramolecular folding-based transcriptional activation system. The system was studied using ER-variants of different lengths, flanked on either side by the GAL4-DNA-binding domain and the VP16-transactivation domain (GAL4(DBD)-ER-VP16). The ER ligands of different types showed efficient ligand-regulated transactivation. We also characterized a bidirectional transactivation system based on the ER and demonstrated its utility in titrating both reporter and therapeutic gene expression. The ligand-regulated transactivation system developed by using a mutant form of the ER (G521T, lacking affinity for the endogenous ligand 17beta-estradiol, whereas maintaining affinity for other ligands) showed efficient activation by the ligand raloxifene in living mice without significant interference from the circulating endogenous ligand. The ligand-regulated transactivation system was used to test the therapeutic efficiency of the tumor suppressor protein p53 in HepG2 (p53(+/+)) and SKBr3 (p53(-/-)/mutant-p53(+/+)) cells in culture and tumor xenografts in living mice. The multifunctional capabilities of this system should be useful for gene therapy applications, to study ER biology, to evaluate gene regulation, ER ligand screening, and ER ligand biocharacterization in cells and living animals.

Abstract

The purpose of this article is to show the value of volumetric oblique coronal reformation of CT data sets for assessing the normal anatomy and abnormalities of the ampulla of Vater.Volumetric oblique coronal reformations are a useful noninvasive method to provide diagnostic information about periampullary abnormalities as well as show secondary features important for local staging and management. The technique is also valuable in providing a time-efficient method to review pertinent findings with clinicians.

Abstract

To evaluate the feasibility of reporter gene imaging in implanted human mesenchymal stem cells (MSCs) in porcine myocardium by using clinical positron emission tomography (PET)-computed tomography (CT) scanning.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Transduction of human MSCs by using different doses of adenovirus that contained a cytomegalovirus (CMV) promoter driving the mutant herpes simplex virus type 1 thymidine kinase reporter gene (Ad-CMV-HSV1-sr39tk) was characterized in a cell culture. A total of 2.25 x 10(6) transduced (n = 5) and control nontransduced (n = 5) human MSCs were injected into the myocardium of 10 rats, and reporter gene expression in human MSCs was visualized with micro-PET by using the radiotracer 9-(4-[fluorine 18]-fluoro-3-hydroxymethylbutyl)-guanine (FHBG). Different numbers of transduced human MSCs suspended in either phosphate-buffered saline (PBS) (n = 4) or matrigel (n = 5) were injected into the myocardium of nine swine, and gene expression was visualized with a clinical PET-CT. For analysis of cell culture experiments, linear regression analyses combined with a t test were performed. To test differences in radiotracer uptake between injected and remote myocardium in both rats and swine, one-sided paired Wilcoxon tests were performed. In swine experiments, a linear regression of radiotracer uptake ratio on the number of injected transduced human MSCs was performed.In cell culture, there was a viral dose-dependent increase of gene expression and FHBG accumulation in human MSCs. Human MSC viability was 96.7% (multiplicity of infection, 250). Cardiac FHBG uptake in rats was significantly elevated (P < .0001) after human MSC injection (0.0054% injected dose [ID]/g +/- 0.0007 [standard deviation]) compared with that in the remote myocardium (0.0003% ID/g +/- 0.0001). In swine, myocardial radiotracer uptake was not elevated after injection of up to 100 x 10(6) human MSCs (PBS group). In the matrigel group, signal-to-background ratio increased to 1.87 after injection of 100 x 10(6) human MSCs and positively correlated (R(2) = 0.97, P < .001) with the number of administered human MSCs.Reporter gene imaging in human MSCs can be translated to large animals. The study highlights the importance of co-administering a "scaffold" for increasing intramyocardial retention of human MSCs.

Abstract

Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.

Abstract

Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.

Abstract

To assess the effect of direct three-dimensional (3D) magnetic resonance (MR) venographic findings on diagnostic thinking and therapeutic decisions in patients with complex recurrent varicose vein anatomy who were being evaluated for surgical treatment.The study was approved by the Institutional Review Board; informed consent was obtained from patients. MR venography was performed before surgery in 22 legs of 14 patients (seven women: mean age, 53 years; seven men: mean age, 59 years) thought to have recurrent varicose veins. Two radiologists assessed image quality and evaluated sites and sources of varicose veins on MR venograms. One vascular surgeon completed a questionnaire before and after MR venography and noted diagnosis and therapeutic decisions. Diagnoses at MR venography were compared with surgical results in 19 legs that underwent surgery. Differences between diagnosed and treated varicose veins per leg before and after MR venography were analyzed with logistic regression for survey data. kappa Values were calculated to illustrate interobserver agreement for grading image quality of venous segments and for diagnosing recurrent varicose veins.Mean graded image quality of the deep venous system and the recurrent varicose veins was good or excellent in 89% of segments. There was good agreement between readers regarding grading of image quality of venous segments (kappa = 0.80). After MR venography, diagnosis of the sites and sources of recurrent varicose veins changed in 17 of 22 legs of nine of 14 patients. In one of 14 patients, the preoperative diagnosis of recurrent varicose veins was withdrawn. A change in treatment plan occurred in 17 of 22 legs after MR venography. The number of diagnosed and treated sources of reflux increased significantly after MR venography. MR venographic diagnoses were confirmed at surgery in all 19 legs.MR venographic results have a substantial effect on diagnostic thinking and therapeutic decisions when recurrent lower-limb varicose veins are suspected.

Abstract

To retrospectively evaluate the performance of breath-hold contrast-enhanced 3D dynamic parallel gradient echo MRI (pMRT) for the characterization of focal liver lesions (standard of reference: histology) and for the analysis of hepatic vasculature (standard of reference: contrast-enhanced 64-detector row computed tomography; MSCT) in a single MRI session.Two blinded readers independently analyzed preoperative pMRT data sets (1.5T-MRT) of 45 patients (23 men, 22 women; 28 - 77 years, average age, 48 years) with a total of 68 focal liver lesions with regard to image quality of hepatic arteries, portal and hepatic veins, presence of variant anatomy of the hepatic vasculature, as well as presence of portal vein thrombosis and hemodynamically significant arterial stenosis. In addition, both readers were asked to identify and characterize focal liver lesions. Imaging parameters of pMRT were: TR/TE/matrix/slice thickness/acquisition time: 3.1 ms/ 1.4 ms/ 384 x 224 / 4 mm/ 15 - 17 s. MSCT was performed with a pitch of 1.2, an effective slice thickness of 1 mm and a matrix of 512 x 512.Based on histology, the 68 liver lesions were found to be 42 hepatocellular carcinomas (HCC), 20 metastases, 3 cholangiocellular carcinomas (CCC) as well as 1 dysplastic nodule, 1 focal nodular hyperplasia (FNH) and 1 atypical hemangioma. Overall, the diagnostic accuracy was high for both readers (91 - 100 %) in the characterization of these focal liver lesions with an excellent interobserver agreement (kappa-values of 0.89 [metastases], 0.97 [HCC] and 1 [CCC]). On average, the image quality of all vessels under consideration was rated good or excellent in 89 % (reader 1) and 90 % (reader 2). Anatomical variants of the hepatic arteries, hepatic veins and portal vein as well as thrombosis of the portal vein were reliably detected by pMRT. Significant arterial stenosis was found with a sensitivity between 86 % and 100 % and an excellent interobserver agreement (kappa = 0.85).Diagnostic image quality remains good or excellent in most cases when the data acquisition time is accelerated by means of parallel imaging in dynamic MRI. It allows reliable detection and characterization of focal liver lesions as well as the depiction of hepatic vascular variants, portal vein thrombosis, and arterial stenosis. Introducing pMRT in routine liver MRI may be another step towards a simplified diagnostic work-up prior to liver surgery.

Abstract

Myocardial infarction (MI) leads to left ventricular (LV) remodeling, which leads to the activation of growth factors such as vascular endothelial growth factor (VEGF). However, the kinetics of a growth factor's receptor expression, such as VEGF, in the living subject has not yet been described. We have developed a PET tracer (64Cu-DOTA-VEGF121 [DOTA is 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid]) to image VEGF receptor (VEGFR) expression after MI in the living subject.In Sprague-Dawley rats, MI was induced by ligation of the left coronary artery and confirmed by ultrasound (n = 8). To image and study the kinetics of VEGFRs, 64Cu-DOTA-VEGF121 PET scans were performed before MI induction (baseline) and on days 3, 10, 17, and 24 after MI. Sham-operated animals served as controls (n = 3).Myocardial origin of the 64Cu-DOTA-VEGF121 signal was confirmed by CT coregistration and autoradiography. VEGFR specificity of the 64Cu-DOTA-VEGF121 probe was confirmed by in vivo use of a 64Cu-DOTA-VEGFmutant. Baseline myocardial uptake of 64Cu-DOTA-VEGF121 was minimal (0.30 +/- 0.07 %ID/g [percentage injected dose per gram of tissue]); it increased significantly after MI (day 3, 0.97 +/- 0.05 %ID/g; P < 0.05 vs. baseline) and remained elevated for 2 wk (up to day 17 after MI), after which time it returned to baseline levels.We demonstrate the feasibility of imaging VEGFRs in the myocardium. In summary, we imaged and described the kinetics of 64Cu-DOTA-VEGF121 uptake in a rat model of MI. Studies such as the one presented here will likely play a major role when studying pathophysiology and assessing therapies in different animal models of disease and, potentially, in patients.

Abstract

The study was approved by the institutional review board, and informed consent was obtained from all patients. The purpose of this study was to retrospectively evaluate the feasibility, reliability, and accuracy of breath-hold dynamic contrast material-enhanced parallel gradient-echo (GRE) magnetic resonance (MR) imaging for mapping the hepatic vascular anatomy, with contrast-enhanced 64-detector row computed tomography (CT) as the reference standard. The parallel GRE MR data sets of 100 patients acquired at 1.5 T were evaluated independently by two blinded readers with respect to (a) image quality for depiction of the hepatic arteries and the portal and hepatic veins and (b) presence of arterial stenosis and variant hepatic vasculature. The readers rated image quality to be good or excellent for 91.1%-100% of the vessels. At parallel GRE MR imaging, the readers diagnosed variant hepatic vessels and arterial stenosis with 94%-100% accuracy. They concluded that parallel GRE MR imaging, as compared with 64-detector row CT, is feasible for hepatic vascular mapping and enables reliable and accurate detection of variant hepatic vasculature and diagnosis of arterial stenosis. Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2453062103/DC1.

Abstract

To prospectively compare the image quality, sensitivity, and specificity of three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography accelerated by parallel acquisition (ie, fast MR angiography) with MR angiography not accelerated by parallel acquisition (ie, conventional MR angiography) for assessment of aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the reference standard.The study was approved by the institutional review board; informed consent was obtained from all patients. Forty consecutive patients (33 men, seven women; mean age, 63 years) suspected of having aortoiliac and renal arterial stenoses and thus examined with DSA underwent both fast (mean imaging time, 17 seconds) and conventional (mean imaging time, 29 seconds) MR angiography. The arterial tree was divided into segments for image analysis. Two readers independently evaluated all MR angiograms for image quality, presence of arterial stenosis, and renal arterial variants. Image quality, sensitivity, and specificity were analyzed on per-patient and per-segment bases for multiple comparisons (with Bonferroni correction) and for dependencies between segments (with patient as the primary sample unit). Interobserver agreement was evaluated by using kappa statistics.Overall, the image quality with fast MR angiography was significantly better (P=.001) than that with conventional MR angiography. At per-segment analysis, the image quality of fast MR angiograms of the distal renal artery tended to be better than that of conventional MR angiograms of these vessels. Differences in sensitivity for the detection of arterial stenosis between the two MR angiography techniques were not significant for either reader. Interobserver agreement in the detection of variant renal artery anatomy was excellent with both conventional and fast MR angiography (kappa=1.00).Fast MR angiography and conventional MR angiography do not differ significantly in terms of arterial stenosis grading or renal arterial variant detection.

Abstract

To evaluate 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) accumulation in human ovarian carcinoma cell lines compared with control tumor cell lines known to accumulate FDG.FDG accumulation assays were performed in 15 different ovarian carcinoma cell lines at 1, 2, and 3 hours after incubation with 1 microCi of FDG. Results were compared with FDG accumulation in six different control tumor cell lines. 2-deoxy-2-[F-18]fluoro-D-glucose accumulation was expressed as counts per minute (cpm) in cells and normalized to initial cpm in medium and total protein content of cell lysates.FDG accumulation in all 15 ovarian carcinoma cell lines was equal to or higher than 0.0005 +/- 8.6 10(-5) cpm in cells/cpm in medium/mug protein at all three different time points. In two ovarian carcinoma cell lines (ES-2, poorly differentiated clear cell carcinoma, and OVCAR-3, poorly differentiated papillary adenocarcinoma), FDG accumulation was not statistically, significantly different compared to the control cell line with the highest FDG accumulation (LS 174T human colorectal adenocarcinoma) at two or more time points (P > or = 0.07). In 2 of 15 (13%) ovarian carcinoma cell lines (OVCAR5 epithelial carcinoma and SKOV3 clear cell carcinoma), FDG accumulation was lower than that in the control cell line with the lowest FDG accumulation (HT-29 human colorectal adenocarcinoma) at one or more time points (P < 0.05).Most human ovarian carcinoma cell lines showed comparable FDG accumulations with control cell lines known to accumulate FDG. This study lays the foundations for further comparisons with other ovarian cancer cell lines and for other positron emission tomography tracers.

Abstract

The purpose of this study was to evaluate a new three-dimensional gradient-echo (GRE) MR sequence performed with a parallel acquisition technique to shorten breath-hold times (parallel GRE MRI) in the detection of arterial variants and stenosis of the abdominal aorta and its visceral branches. A total of 102 patients underwent dynamic parallel GRE MRI, timed to the arterial phase by a test bolus (mean breath-hold time, 17 s). For both quantitative and qualitative analysis, the abdominal aorta and its visceral branches were divided into 13 arterial segments. In a subanalysis of 55/102 patients, the accuracy of parallel GRE MRI compared to MDCT in the detection arterial variants and stenosis was calculated for two independent readers. Mean SNRs and CNRs were 47.2 and 35.6, respectively. Image quality was rated good or excellent in 1,234/1,326 segments (93%). Hepatic and renal arterial variants were identified with an accuracy of 93 and 95%, respectively (reader 1) and 98 and 100%, respectively (reader 2). Both readers detected arterial stenosis with an accuracy of 98%. Interobserver agreement was good to excellent for the detection of hepatic (kappa=0.69) and renal (kappa=0.92) variants and for the diagnosis of stenosis (kappa=0.96). Dynamic three-dimensional parallel GRE MRI is feasible and allows a reliable and accurate diagnosis of arterial variants and stenosis of the abdominal aorta and its visceral branches in a short breath-hold-time.

Abstract

The purpose of this study was to compare respiratory-triggered balanced steady-state free precession (bSSFP) with breath-hold contrast-enhanced dynamic two-dimensional (2D) gradient-echo (GRE) and time-of-flight (TOF) magnetic resonance imaging (MRI) for portal and hepatic vein visualization and assessment of portal and hepatic venous variants. Sixty patients with liver disease underwent nonenhanced bSSFP and contrast-enhanced GRE, bSSFP, and TOF imaging. Contrast-to-noise ratios (CNRs) for portal and hepatic veins were measured. Two readers rated the quality of portal and hepatic vein visualization on a 5-point Likert scale. The diagnostic performance of each MRI series in the detection of portal and hepatic venous variants was assessed in 40/60 patients who also underwent contrast-enhanced multidetector-row computed tomography (MDCT). CNRs for portal and hepatic veins were highest on contrast-enhanced bSSFP images. Image quality of portal and hepatic veins was rated higher for nonenhanced bSSFP than for contrast-enhanced GRE (p<0.03) and TOF (p<0.003) and higher for contrast-enhanced than for nonenhanced bSSFP (p<0.003). Compared with MDCT, portal and hepatic venous variants were identified with an accuracy of 99% on bSSFP images, with an excellent interobserver agreement (kappa=0.97). Compared with MDCT, presence of surgically important portal and hepatic venous anatomical variants can be predicted with high accuracy on bSSFP images.

Abstract

Venous anomalies are rare causes of ureteral obstruction. We report the case of a 31-year-old woman with obstruction of the right distal ureter by a complex pelvic venous anomaly. Beside benign and malignant lesions of the retroperitoneum, venous anomalies should also be considered in the differential diagnosis of extrinsic ureteral obstruction. Due to its abilities of three-dimensional visualization, multi-detector row computed tomography is helpful in the depiction of venous anomalies.

Abstract

With the introduction of multidetector-row CT (MDCT) technology indications for MDCT angiography have expanded to include assessment of the peripheral arteries of the upper and lower extremities. Combined with patient- and scanner-adjusted CT data acquisition and contrast medium application strategies, an accurate and reliable evaluation of the peripheral arteries of the upper and lower extremities is possible. MDCT angiography is cost-effective and accurate for detection of arterial stenosis and occlusion in patients with peripheral arterial disease (PAD). MDCT angiography allows postoperative assessment of peripheral arterial bypass grafts, including bypass graft stenosis and occlusion, as well as presence of aneurysms or arteriovenous fistulas. In addition, MDCT angiography is helpful in particular for visualization of arterial bypass grafts with a complicated extra-anatomical course. Furthermore, pre-operative peripheral vascular mapping can be performed by using MDCT angiography. Finally, due to the integration of MDCT scanners in many trauma centres, MDCT angiography is increasingly being used for assessment of traumatic arterial injuries. This article gives an overview of technical aspects of peripheral MDCT angiography, including scanning parameters, contrast medium application, image postprocessing and radiation exposure, and summarizes the most frequent acute and non-acute indications of MDCT angiography for assessment of the upper- and lower-extremity peripheral arteries.

Abstract

To evaluate the influence of different reconstruction intervals of retrospectively electrocardiographically (ECG)-gated multi-detector row computed tomographic (CT) angiography on image quality of different segments of various types of coronary artery bypass grafts.Twenty consecutive patients with 62 grafts underwent retrospectively ECG-gated four-channel multi-detector row CT angiography and conventional coronary angiography. Raw helical CT data were reconstructed at 0%-90% of the cardiac cycle in increments of 10%. Each graft was separated into three segments (proximal segment, graft body, and distal anastomosis). Three graft types were identified according to site of distal anastomosis. Two readers assessed image quality of segments and graft types. Effective radiation dose was calculated.Best image quality of all segments was obtained at a reconstruction interval of 50%-70% of the cardiac cycle. Image quality of the proximal segment did not vary significantly with different reconstruction intervals (analysis of variance, P =.8), whereas image quality of the graft body and distal anastomosis changed significantly with varying reconstruction intervals (P

Abstract

Our goal was to determine the impact of ECG gating and different postprocessing techniques on 3D imaging of the bronchial tree. SUBJECTS AND METHODS. Retrospective ECG-gated MDCT and non-ECG-gated MDCT of the chest were performed in 25 patients. ECG-gated MDCT data were reconstructed mid diastole using a fixed interval of -400 msec in 25 patients and then additionally at -200, -300, and -500 msec in 10 of those patients. Shaded surface display and volume rendering of the bronchial tree combined with virtual bronchoscopy were performed using all data sets. The extent of bronchial tree visualization in shaded surface display-virtual bronchoscopy and volume rendering-virtual bronchoscopy and the presence of artifacts in volume-rendered images were scored by three blinded reviewers. The effective radiation doses of the ECG-gated and nongated acquisitions were compared.The summary scores of all bronchial segments for gated shaded surface display-virtual bronchoscopy and gated volume rendering-virtual bronchoscopy did not differ significantly. The summary scores for nongated shaded surface display-virtual bronchoscopy and nongated volume rendering-virtual bronchoscopy were not significantly different. Non-gated acquisition yielded significantly better visualization of the bronchial tree for both post-processing techniques, regardless of the time interval used for reconstruction of the ECG-gated series. Artifact scores in volume-rendered images were significantly higher for ECG-gated MDCT compared with nongated MDCT. Effective radiation dose was significantly higher for the ECG-gated acquisition.Given the advantage of volume rendering for representing the entire data set and given the lower radiation dose and better 3D image quality of nongated acquisition, volume rendering performed on nongated MDCT data is the method of choice for 3D visualization of the bronchial tree.

Abstract

To evaluate the time-effectiveness, inter-observer variance, and accuracy of left ventricular ejection fraction (EF) measurements using retrospectively ECG-gated four-channel multi-detector row CT (MDCT) angiography in comparison with biplane cine-ventriculography.Twenty consecutive patients underwent retrospectively ECG-gated MDCT angiography and conventional coronary angiography with biplane ventriculography. Raw MDCT data were reconstructed at 0 % - 90 % of the cardiac cycle in increments of 10 %. Ten geometrically identical multiplanar reformations parallel to the short axis of the heart were reconstructed in each patient. Three blinded readers segmented the left ventricle in the end-systolic and end-diastolic phase using standardized window settings in order to determine the EF. The EF was measured with biplane cine-ventriculography by two blinded readers and was compared with MDCT. The time needed for post-processing was recorded and the inter-observer agreement for both imaging techniques was assessed.Mean post-processing time was 63 +/- 3 min per patient for MDCT and 5.5 +/- 1.2 min for ventriculography. MDCT and ventriculography showed a good correlation (r = 0.83, p < 0.0001) for measurement of the EF. Mean errors of EF measurements for the three MDCT readers compared with the mean of the ventriculography were - 6.3 +/- 6.6 %, - 4.7 +/- 7.1 % and - 4.6 +/- 5.7 %, respectively. The mean differences between the three readers assessing MDCT were - 1.6 +/- 3.2 % (reader 1 versus 2, r = 0.96), - 1.6 +/- 5.6 % (1 versus 3, r = 0.95) and - 0.011 +/- 2.9 % (2 versus 3, r = 0.97, p < 0.0001). The mean differences between the two readers assessing ventriculography was 0.32 +/- 5.1 % (r = 0.88, p < 0.0001).MDCT correlates well with biplane cine-ventriculography but has the tendency to underestimate the left ventricular EF. Measurements using MDCT have a high inter-observer agreement, however, the time needed for additional MDCT data post-processing is still unacceptably long.

Abstract

To determine the impact of retrospectively ECG-gated multi-detector row CT (MDCT) on three-dimensional (3D) visualization of the bronchial tree and virtual bronchoscopy (VB) as compared to non-ECG-gated data acquisition.Contrast-enhanced retrospectively ECG-gated and non-ECG-gated MDCT of the chest was performed in 25 consecutive patients referred for assessment of coronary artery bypass grafts and pathology of the ascending aorta. ECG-gated MDCT data were reconstructed in diastole using an absolute reverse delay of - 400 msec in all patients. In 10 patients additional reconstructions at - 200 msec, - 300 msec, and - 500 msec prior to the R-wave were performed. Shaded surface display (SSD) and virtual bronchoscopy (VB) for visualization of the bronchial segments was performed with ECG-gated and non-ECG-gated MDCT data. The visualization of the bronchial tree underwent blinded scoring. Effective radiation dose and signal-to-noise ratio (SNR) for both techniques were compared.There was no significant difference in visualizing single bronchial segments using ECG-gated compared to non-ECG-gated MDCT data. However, the total sum of scores for all bronchial segments visualized with non-ECG-gated MDCT was significantly higher compared to ECG-gated MDCT (P < 0.05). The summary scores for visualization of bronchial segments for different diastolic reconstructions did not differ significantly. The effective radiation dose and the SNR were significantly higher with the ECG-gated acquisition technique (P < 0.05).The bronchial tree is significantly better visualized when using non-ECG-gated MDCT compared to ECG-gated MDCT. Additionally, non-ECG-gated techniques require less radiation exposure. Thus, the current retrospective ECG-gating technique does not provide any additional benefit for 3D visualization of the bronchial tree and VB.

Abstract

To assess the technical feasibility of multi-detector row computed tomographic (CT) angiography in the assessment of peripheral arterial bypass grafts and to evaluate its accuracy and reliability in the detection of graft-related complications, including graft stenosis, aneurysmal changes, and arteriovenous fistulas.Four-channel multi-detector row CT angiography was performed in 65 consecutive patients with 85 peripheral arterial bypass grafts. Each bypass graft was divided into three segments (proximal anastomosis, course of the graft body, and distal anastomosis), resulting in 255 segments. Two readers evaluated all CT angiograms with regard to image quality and the presence of bypass graft-related abnormalities, including graft stenosis, aneurysmal changes, and arteriovenous fistulas. The results were compared with McNemar test with Bonferroni correction. CT attenuation values were recorded at five different locations from the inflow artery to the outflow artery of the bypass graft. These findings were compared with the findings at duplex ultrasonography (US) in 65 patients and the findings at conventional digital subtraction angiography (DSA) in 27.Image quality was rated as good or excellent in 250 (98%) and in 252 (99%) of 255 bypass segments, respectively. There was excellent agreement both between readers and between CT angiography and duplex US in the detection of graft stenosis, aneurysmal changes, and arteriovenous fistulas (kappa = 0.86-0.99). CT angiography and duplex US were compared with conventional DSA, and there was no statistically significant difference (P >.25) in sensitivity or specificity between CT angiography and duplex US for both readers for detection of hemodynamically significant bypass stenosis or occlusion, aneurysmal changes, or arteriovenous fistulas. Mean CT attenuation values ranged from 232 HU in the inflow artery to 281 HU in the outflow artery of the bypass graft.Multi-detector row CT angiography may be an accurate and reliable technique after duplex US in the assessment of peripheral arterial bypass grafts and detection of graft-related complications, including stenosis, aneurysmal changes, and arteriovenous fistulas.

Abstract

To determine the impact of prospective electrocardiographic (ECG) triggering on image quality and diagnostic outcome of thin-section computed tomography (CT) of the lung.Forty-five consecutive patients referred for thin-section CT of the lung were examined with prospectively ECG-triggered and nontriggered thin-section CT of the lung with a multi-detector row helical CT scanner. Subjective image quality criteria (image noise, motion artifacts, and diagnostic accessibility) were rated by three radiologists in consensus for the upper lobe, middle lobe and/or lingula, and lower lobe. Pathologic changes were assessed for the various lobes, and a diagnosis was assigned. The diagnoses were compared by two radiologists in consensus to determine the effects of CT technique on diagnostic outcome. Quantitative measurements were performed, including determination of image noise and signal-to-noise ratios in different anatomic regions. The Wilcoxon signed rank test and paired sign test (both with Bonferroni correction) were used for statistical analysis.Subjective assessment showed significant differences in motion artifact reduction in the middle lobe, lingula, and left lower lobe. The diagnostic assessibility of triggered CT was rated significantly higher only for the left lower lobe compared with nontriggered data acquisition. No differences in diagnostic outcome were determined between triggered and nontriggered techniques. Mean image noise in tracheal air was 68.2 +/- 17 (SD) for triggered CT versus 37.4 +/- 9 for nontriggered CT (P

Abstract

The diagnosis of submucosal fundal varices is challenging. Currently, endoscopy and endoscopic ultrasound (EUS) are considered most useful for this purpose. The aim of this study was to evaluate if multi-detector row CT (MDCT) angiography contributes to the diagnosis of submucosal fundal varices.Twenty two patients with endoscopically suspected fundal varices were prospectively included in the study. All patients underwent EUS and MDCT angiography. Levels of agreement between EUS and MDCT angiography for the detection of submucosal and perigastric fundal varices were evaluated by three blinded independent readers. In addition, variceal size and location, as well as afferent and efferent vessels of the submucosal varices, were determined.Good or excellent image quality of MDCT angiography was obtained in 21/22 patients (95%). Based on EUS, submucosal varices were detected in 16 of 22 patients (73%) and perigastric varices in 22/22 patients (100%). Using MDCT angiography, the presence of submucosal varices was confirmed in all of these 16 patients by all three readers. Perigastric varices were also confirmed in all 22 patients by all three readers. In addition, all three readers noted the presence of a submucosal varix in an additional patient which was not detected on initial EUS. MDCT angiography showed an excellent interobserver reliability with regard to variceal diameter (kappa=0.90) and variceal location (kappa=0.94). Based on MDCT angiography, afferent and efferent vessels of submucosal varices included the left gastric vein in 11 (65%), the posterior/short gastric veins in 15 (88%), gastrorenal shunts in 10 (59%), the left inferior phrenic vein in six (35%), and the left pericardiophrenic vein in six (35%) of 17 patients.MDCT angiography is equivalent to EUS in terms of detection and characterisation of fundal varices, in particular with regard to the distinction between submucosal and perigastric fundal varices.

Abstract

To evaluate contrast-enhanced MR angiography for the distinction between perigastric and submucosal fundal varices.Nineteen consecutive patients with clinically suspected fundal varices underwent contrast-enhanced MR angiography and endoscopic ultrasound (EUS) within one week. Diagnostic confidence for the detection of perigastric and submucosal fundal varices was compared between MR angiography (two radiologists) and EUS (one gastroenterologist), and the agreement of size and location was evaluated.Both MR angiography and EUS detected perigastric varices in all 19 patients and submucosal fundal varices in 14 of the 19 patients. The interobserver reliability of MR angiography was good for measuring the variceal diameter (kappa = 0.76) and excellent for localizing the varices (kappa = 1.0). EUS and MR angiography agreed in 12 of 14 patients (86 %) in determining variceal diameter and location.Contrast-enhanced MR angiography is comparable to endoscopic ultrasound in the detection and characterization of gastric fundal varices.

Abstract

The purpose of this study was to assess accuracy and reliability of a volumetric analysis of abdominal aneurysms on the basis of multidetector row computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) with a commercially available automated vessel analysis software program.Twenty patients with abdominal aortic aneurysms underwent preoperative CTA and MRA before endovascular repair. Postdeployment CTA was performed in 15 of these 20 patients (75%). All preoperative CTA and MRA and postdeployment CTA data sets were analyzed with an automated software tool. The length of the stent grafts on postdeployment CTA was measured and compared with the true length of the primary component. Two readers independently evaluated 13 vessel parameters on preoperative CTA and MRA, which are considered to be important in planning stent graft deployment.With the automated analysis software tool, all measurements could be performed on either CTA or MRA data sets. There was no statistically significant difference between postdeployment measurements of stent graft length on CTA and the true dimensions of the implanted stent grafts. Interobserver agreement for all of the measurements with either CTA or MRA was good to excellent (interclass coefficient, 0.71 to 0.99) with only minimal mean differences of measured dimensions between both readers (range, -2.0 to +2.3 mm, Bland-Altman). Intermodality agreement between CTA and MRA was good to excellent (interclass coefficient, 0.62 to 0.98) with small mean differences of measured dimensions between both methods (range, -4.1 to +2.1 mm, Bland-Altman).Volumetric measurement with an automated analysis software tool allows a fast, precise, and reliable noninvasive preoperative determination of all aortic dimensions on the basis of either CTA or MRA data sets.

Abstract

To assess the effect of prone, supine, and upright weight-bearing body positions on visibility, position, shape, and size of Morton neuroma during magnetic resonance (MR) imaging.Eighteen patients with 20 Morton neuromas underwent MR imaging of the forefoot in prone (plantar flexion of the foot), supine (dorsiflexion of the foot), and upright weight-bearing positions. Visibility (3 = good, 2 = moderate, 1 = poor), position relative to the metatarsal bone, shape, and transverse diameter of Morton neuroma were assessed on transverse T1-weighted MR images. Associations between different body positions and variables of interest were calculated with Wilcoxon signed rank test, chi2 test, and paired Student t test.In the prone position, visibility of all 20 Morton neuromas was rated with a score of 3; visibility in the supine and weight-bearing positions was inferior (mean score, 2.4). All 20 (100%) Morton neuromas changed their position relative to the metatarsal bone between prone and supine and between prone and weight-bearing positions. When compared with the prone position, there was a difference in the shape of all 20 Morton neuromas in the weight-bearing position (P

Abstract

To compare contrast material-enhanced three-dimensional (3D) magnetic resonance (MR) angiography and multi-detector row computed tomographic (CT) angiography in the same patients for assessment of the aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the standard of reference.DSA, 3D MR angiography, and multi-detector row CT angiography were performed in 46 consecutive patients. A total of 769 arterial segments were analyzed for arterial stenosis by using a four-point grading system. Aneurysmal changes were noted. The time required for performing 3D reconstructions and image analysis of both MR and CT data sets was measured. Patient acceptance for each modality was assessed with a visual analogue scale. Statistical analysis of data was performed.Sensitivity of MR angiography for detection of hemodynamically significant arterial stenosis was 92% for reader 1 and 93% for reader 2, and specificity was 100% and 99%, respectively. Sensitivity of CT angiography was 91% for reader 1 and 92% for reader 2, and specificity was 99% and 99%, respectively. Differences between the two modalities were not significant. Interobserver and intermodality agreement was excellent (kappa = 0.88-0.90). The time for performance of 3D reconstruction and image analysis of CT data sets was significantly longer than that for MR data sets (P

Abstract

We report a case of active bleeding of a secondary aortoenteric fistula (SAEF), in which CT angiography with multi-detector-row CT (MDCT) was finally diagnostic after negative catheter angiography and unsatisfactory endoscopy. The MDCT angiography clearly demonstrated the fistulous tract between the abdominal aortic graft and the duodenum. The dynamic process of bleeding was confirmed as a net increase of contrast agent accumulation in the duodenum through different phases. The MDCT angiography with its excellent 3D image quality is therefore a valuable method in the assessment of active SAEF bleeding.

Abstract

Our objective was to evaluate applicability and image quality of contrast-enhanced, retrospectively ECG-gated multi-detector row CT (MDCT) for visualization of anatomical details of the mitral valve and its apparatus, and to determine the value of MDCT for diagnosing abnormal findings of the mitral valve. Twenty consecutive patients with mitral valve disease underwent MDCT preoperatively. Two readers assessed visibility of the mitral valve annulus, mitral valve leaflets, tendinous cords, and papillary muscles by using a four-point Likert grading scale. Abnormal mitral valve findings [thickening of the mitral valve leaflets, presence of mitral annulus calcification (MAC), and calcification of the valvular leaflets] were compared with preoperative echocardiography and intraoperative findings. Visibility of the mitral valve annulus and mitral valve leaflets was good or excellent in 15 patients (75%) and in 19 patients (95%) for papillary muscles. The MDCT yielded a 95-100% agreement compared with echocardiography and surgery with regard to the assessment of mitral valve leaflet thickening and the presence of calcifications of the mitral valve annulus or mitral valve leaflets. Intermodality agreement between MDCT and echocardiography was excellent with regard to classification of mitral valve leaflet thickness (kappa=1.00) and good regarding classification of MAC thickness (kappa=0.73). Contrast-enhanced, retrospectively ECG-gated MDCT allows good to excellent visualization of anatomical details of the mitral valve and its apparatus, and demonstrates good agreement with echocardiography and surgery in diagnosing mitral valve abnormalities.

Abstract

To evaluate the applicability and image quality of nonenhanced and contrast material-enhanced multi-detector row computed tomography (CT) combined with retrospective electrocardiographic (ECG) gating for visualization of the aortic valve, determination of aortic valve morphology and diameter of the aortic valve annulus, and assessment of the degree of valvular calcification in patients with aortic valve stenosis, as compared with results of surgery and echocardiography.Prior to surgical valve replacement, 25 patients with aortic valve stenosis and sinus rhythm underwent nonenhanced (n = 15) and contrast-enhanced (n = 25) retrospectively ECG-gated multi-detector row CT. Two readers working in consensus evaluated image quality and assessed valvular morphology and the degree of valvular calcification. In addition, the diameter of the aortic valve annulus was measured. Results were compared with surgical and echocardiographic findings by using the paired sign test, kappa statistics, and the method of Bland and Altman.The aortic valve could be visualized nearly free of motion artifacts on all multi-detector row CT images. Image quality and diagnostic confidence for classification of aortic valve morphology were significantly superior on contrast-enhanced rather than nonenhanced images (P =.004 and P =.006, respectively). Nonenhanced and contrast-enhanced CT showed good agreement with surgical findings with regard to quantification of the degree of aortic valve calcification (kappa = 0.77 and kappa = 0.74, respectively). Measurement of the diameter of the aortic valve annulus was more reliable on contrast-enhanced images.Contrast-enhanced retrospectively ECG-gated multi-detector row CT allows determination of aortic valve morphology, measurement of the diameter of the aortic valve annulus, and assessment of the degree of aortic valve calcification in patients with aortic stenosis.

Abstract

The aim of this study was to determine the imaging findings and the prevalence of active hemorrhage on contrast-enhanced multidetector CT in patients with blunt abdominal trauma.Contrast-enhanced multidetector CT images of 165 patients with blunt abdominal trauma were reviewed for the presence of extravasated contrast agent, a finding that represents active hemorrhage. The site and appearance of the hemorrhage were noted on multidetector CT images. These findings were compared with surgical and angiographic results or with clinical follow-up.On multidetector CT images, active hemorrhage was detected in 22 (13%) of 165 patients with a total of 24 bleeding sites (14 intraperitoneal sites and 10 extraperitoneal sites). Active hemorrhage was visible most frequently as a jet of extravasated contrast agent (10/24 bleeding sites [42%]). Diffuse or focal extravasation was less frequently seen (nine [37%] and five [21%] bleeding sites, respectively). CT attenuation values measured in the aorta (mean, 199 H) were significantly higher than those measured in extravasated contrast material (mean, 155 H) (p < 0.001). Sixteen (73%) of 22 patients with active bleeding on multidetector CT images underwent immediate surgical or angiographic intervention. One patient received angiographic therapy 10 hr after undergoing multidetector CT, and five patients died between 1 and 3 hr after multidetector CT examination.Active hemorrhage in patients after blunt abdominal trauma is most frequently visible as a jet of extravasated contrast agent on multidetector CT. When extravasation is detected, immediate surgical or angiographic therapy is required.

Abstract

Functional disorders of the pelvic floor are a common clinical problem. Diagnosis and treatment of these disorders, which frequently manifest with nonspecific symptoms such as constipation or incontinence, remain difficult. Fluoroscopic x-ray defecography has been shown to aid in detection of functional and morphologic abnormalities of the anorectal region. With the advent of open-configuration magnetic resonance (MR) imaging systems, MR defecography with the patient in a vertical position became possible. MR defecography permits analysis of the anorectal angle, the opening of the anal canal, the function of the puborectal muscle, and the descent of the pelvic floor during defecation. Good demonstration of the rectal wall permits visualization of intussusceptions and rectoceles. Excellent demonstration of the perirectal soft tissues allows assessment of spastic pelvic floor syndrome and descending perineum syndrome and visualization of enteroceles. MR defecography with an open-configuration magnet allows accurate assessment of anorectal morphology and function in relation to surrounding structures without exposing the patient to harmful ionizing radiation.

Abstract

The availability of new imaging modalities has altered the diagnostic approach to patients with abdominal and pelvic trauma. Computed tomography and ultrasound have largely replaced diagnostic peritoneal lavage. Ultrasound is used in most trauma centers as the initial imaging technique for the detection of hemoperitoneum and helps to determine the need for emergency laparotomy. Computed tomography allows for an accurate diagnosis of a wide range of traumatic abdominal and pelvic conditions. The speed of single-detector helical and multi-detector row CT (MDCT) permits a rapid CT examination of the seriously ill patient in the emergency room. In particular, the technology of MDCT permits multiple, sequential CT scans to be quickly obtained in the same patient, which is a great advance in the rapid assessment of the multiple-injured patient. The evolving concepts in trauma care promoting non-operative management of liver and splenic injuries creates the need for follow-up cross-sectional imaging studies in these patients. Computed tomography and, less frequently, MR or ultrasound, are used for this purpose.

Abstract

The purpose of this study was to evaluate time management and workflow for multidetector-row helical CT (MDCT). Time for patient and data handling of at total of 580 patients were evaluated at two different time periods (December 1999, August 2000), each for the following baseline measurements: (a) change of clothes/instruction; (b) patient placement on the CT table/i.v. catheter; (c) CT planning and programming; (d) CT data acquisition; (e) CT data reconstruction; (f) CT data storage/printing. All imaging was performed on a Somatom Volume Zoom (Siemens, Erlangen, Germany). Time measurements summarized for different CT protocols revealed the following: (a) 5:01 min (+/- 2.06 min); (b) 4:36 min (+/- 2.43 min); (c) 4:11 min (+/- 2.55 min); (d) 0:43 min (+/- 0.15 min); (e) 6:59 min (+/- 2.39 min); (f) 09:51 min (+/- 3.51 min). Planning and programming was most time-consuming for CT angiography, whereas chest and abdominal CT needed only 3:26 and 3:30 min, respectively. Reconstruction time was highest for HRCT (9:22 min) and CTA (9:03 min). Data storage/printing was most time-consuming for HRCT (13:02 min), followed by combined neck-chest-abdomen examinations (12:19 min). Comparing the two time periods, during which a software update was performed, a mean time reduction of 4:31 min per patient (15%, p<0.001) was achieved. Whereas CT data acquisition time is no longer a problem with MDCT, patient management, data reconstruction, and data storage are the most time-consuming parts. Well-trained technicians, state-of-the-art workstations, and fast networking are the most important factors to improve workflow.

Abstract

Tracheal involvement is an extremely rare manifestation in patients with neurofibromatosis type 1 (NF-1). We present a 33-year-old women with NF-1 suffering from progressive dyspnea. Multislice spiral CT revealed a neurofibroma located within the trachea with intratracheal extension. To our knowledge, this is the first report of an intratracheal neurofibroma which has been documented by CT. This indicates that multislice spiral CT allows accurate demonstration of localization and extent of this rare manifestation of neurofibromas.

Abstract

To evaluate spiral computed tomography (SCT) angiography for assessment of feasibility of endovascular aneurysm repair (EVAR) in patients with ruptured aortoiliac aneurysm (AAA).24 patients (mean age 74 years; range, 69 to 82 years) with suspicion of ruptured AAA and stable hemodynamics were preoperatively examined by using a SCT scanner in the emergency room. SCT angiography was performed from the suprarenal aorta to the femoral bifurcation after a fixed injection delay time of 30 seconds. After that a venous phase SCT scan, beginning at the last image position and ending at the upper thoracic aperture, was performed.The mean acquisition time of the SCT scan was 80 seconds (range 70 to 100 seconds), the mean overall procedure time, including image reconstruction, 5 minutes (range, 4 to 6 minutes). 2D images were directly evaluated during CT data acquisition, and 3D image reconstructions within 10 minutes (range, 8 to 11 minutes) after the SCT scan. AAA rupture was assessed in 14/24 patients (58%): in 10/14 patients (71%) rupture was contained to the retroperitoneum, and in 4/14 patients (29%) intraperitoneal rupture was observed. Successful EVAR was performed in 6/14 patients (43%) with ruptured AAA, and in 8/10 patients (80%) without ruptured AAA. Open surgery was exclusively performed in 6/24 patients (25%) with inappropriate anatomy for EVAR and in 4/24 patients (17%) with intraperitoneal rupture.Spiral computed tomography angiography is a reliable technique to assess feasibility of endovascular aneurysm repair in patients with ruptured aortic aneurysm. However, it can only be recommended for patients with stable hemodynamics, despite of the short acquisition time.

Abstract

Perforation, a severe complication of necrotizing enterocolitis (NEC), has a high mortality rate. Recently, we presented a new technique for evaluation of NEC: measuring the CT attenuation coefficient of urine after oral administration of iohexol. We present three cases of neonates with NEC who demonstrated serial increases in urine CT attenuation coefficients, all of whom subsequently deteriorated clinically and radiographically. Surgery in all three cases confirmed severe necrosis and/or perforation. These three cases suggest that the CT attenuation coefficient of urine after oral administration of iohexol may be a more sensitive indicator of NEC severity, progression, and perforation than clinical evaluation and radiography. More investigation is necessary, but eventually, this noninvasive technique may be able to decrease morbidity and mortality by predicting the need for surgical intervention or more aggressive medical management of NEC before perforation occurs.

Abstract

Meconium peritonitis is a chemical peritonitis which occurs following bowel perforation during fetal life. It is generally looked upon as benign, resulting in no long-term sequelae. We present a case of a newborn infant with meconium peritonitis who developed infarcts in several organs. At autopsy the infarcts proved to be caused by emboli as a result of intravascular dissemination of meconium. To our knowledge, this is the first reported case of systemic spread of meconium peritonitis in the literature and suggests that meconium peritonitis may have more serious implications than generally thought.

Abstract

Previous single-channel recordings from the luminal membrane of the rabbit proximal tubule have revealed amiloride-inhibitable Na+ channels of a characteristic conductance range. The present study aimed to pursue this issue in rat proximal tubule. Control rats were compared to those put on a low-Na+ diet or pretreated by triamcinolone injections (s.c.). Stimulation of Na+ absorption by glucocorticoids was verified by examining the transepithelial voltage in Ussing chamber studies of the distal colon. The membrane voltage (Vm) of isolated, in-vitro-perfused proximal tubule segments was measured in patch-clamp and impalement studies. It was found that amiloride hyperpolarized Mv significantly by 2.1 +/- 0.9 mV (n = 26) in tubules of control rats, by 3.9 +/- 0.7 mV (n = 12) in rats put on a low-Na+ diet and by 3.7 +/- 1.0 mV (n = 17) in rats treated with glucocorticoids. The effect of amiloride was concentration dependent with a half-maximal effect at < 1 micromol/l. RT-PCR techniques were used to search for the presence of the alpha-, beta- and gamma-subunits of the epithelial Na+ channel in isolated proximal tubule segments. The presence of the respective mRNAs was verified. These data indicate that: (1) amiloride-inhibitable Na+ channels are present in rate proximal tubules; (2) the Na+ conductance may be up-regulated by Na+ deprivation but is still very limited when compared to total cell conductance; (3) therefore, the contribution of Na+-channel-mediated absorption to total proximal Na+ absorption is probably small.